Cited by 24Carbohydrate Chemistry and SynthesisNatural Antidiabetic Agents StudiesEnzyme Structure and Function

In situ extension as an approach for identifying novel α-amylase inhibitors.

Open access
Numao, Shin, Damager, Iben, Li, Chunmin, Wrodnigg, Tanja M., Begum, Anjuman, Overall, Christopher M., Brayer, Gary D., Withers, Stephen G.·2004·Journal of Biological Chemistry

Abstract

A new approach for the discovery and subsequent structural elucidation of oligosaccharide-based inhibitors of alpha-amylases based upon autoglucosylation of known alpha-glucosidase inhibitors is presented. This concept, highly analogous to what is hypothesized to occur with acarbose, is demonstrated with the known alpha-glucosidase inhibitor, d-gluconohydroximino-1,5-lactam. This was transformed from an inhibitor of human pancreatic alpha-amylase with a K(i) value of 18 mm to a trisaccharide analogue with a K(i) value of 25 mum. The three-dimensional structure of this complex was determined by x-ray crystallography and represents the first such structure determined with this class of inhibitors in any alpha-glycosidase. This approach to the discovery and structural analysis of amylase inhibitors should be generally applicable to other endoglucosidases and readily adaptable to a high throughput format.

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Crossref · 10.1074/jbc.m406804200

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  • The initial automatic preparation of structures performed by PDBbind did not provide an optimized hydrogen bond network and appropriate assignment of protonation/tautomeric states of the α-amylase and MeG2-GHIL complex.

    “For example, the initial automatic preparation of the structures performed by PDBbind did not provide an optimized hydrogen bond network and appropriate assignment of protonation/tautomeric states of the α-amylase and MeG2-GHIL complex [Figure 1, PDB code 1U33; Numao et al., 2004].”

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  1. Henrissat, B., Callebaut, I., Fabrega, S., Lehn, P., Mornon, J. P., and Davies, G. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 7090 -7094

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Authors
Numao, S., Damager, I., Li, C., Wrodnigg, T. M., Begum, A., Overall, C. M., Brayer, G. D., & Withers, S. G.
Affiliations
University of British Columbia (CA)
Corresponding author
Withers, Stephen G.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2004-11
Volume
279
Issue
46
Pages
48282-48291
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2041943011
Cited by
24
References
38
Citations by year
2026: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 2 · 2019: 1 · 2018: 2 · 2016: 1 · 2014: 4 · 2012: 2
FWCI
0.00
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Carlsbergfondet
  • Canadian Institutes of Health Research
Topics
  • Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
alpha-amylase inhibitors, alpha-glucosidase inhibitors, acarbose, pancreatic alpha-amylase, enzyme-inhibitor complex structure
MeSH terms
alpha-Amylases, Animals, Binding Sites, Carbohydrate Sequence, Enzyme Inhibitors, Humans, Models, Molecular, Pancreas, Protein Binding, Trisaccharides, Drug Design, Molecular Structure, Protein Structure, Tertiary, Crystallography, X-Ray, Acarbose

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